Cordycepin and preparation method thereof

Abstract

The invention relates to the field of biochemistry, in particular to cordycepin and a preparation method thereof. The catalyst applied to cordycepin comprises red phosphorus or / and black scale. The preparation method comprises the following step: carrying out reduction reaction on a halogenated product of organic acylated adenosine, a catalyst and a reducing agent under light irradiation to obtain the cordycepin. The dehalogenation reaction is promoted through a photocatalysis mechanism under the irradiation of light. Under the irradiation of light, halide ions in the halogenated product are effectively removed to form cordycepin. Light irradiation can excite red phosphorus to generate free radicals, the free radicals are transmitted to a reducing agent (such as rongalite to generate sulfur dioxide free radicals) through electrons, the cordycepin can be stably prepared, the purity of the cordycepin reaches 95% or above, and the yield can reach 82%.

Description

Technical Field

[0001] The present invention relates to the field of biochemistry, and in particular to cordycepin and a preparation method thereof. Background Art

[0002] Cordycepin is an important biologically active substance extracted from Cordyceps sinensis, which has multiple biological activities such as anti-tumor and anti-viral. The preparation methods of cordycepin usually include natural extraction, chemical synthesis and enzyme catalysis synthesis.

[0003] The natural extraction method is to extract cordycepin from the fruiting body or mycelium of Cordyceps militaris, and commonly used solvents (such as ethanol, water) are extracted and combined with chromatographic purification. However, this method is highly dependent on raw materials, the growth cycle of Cordyceps militaris is long (≥60 days), and the cordycepin content is low (usually <1% dry weight); the extraction steps are complicated, the solvent consumption is large, and the purification cost is high; it is difficult to scale up production. The microbial fermentation method is to use genetically engineered bacteria or Cordyceps militaris mycelium to ferment and produce cordycepin. The yield of cordycepin in wild strains is low (usually <500 mg / L), and mutagenesis or genetic modification is required; the fermentation conditions are harsh (such as oxygen control, temperature control, and specific inducers), and the process stability is poor; downstream separation and purification is difficult, and the cost is high. The enzyme catalysis method uses enzymes such as adenosine deaminase to catalyze the conversion of precursor substances to generate cordycepin. The enzyme has poor stability and limited reaction conditions (such as temperature and pH); the enzyme manufacturing cost is high, and it is difficult to scale up industrially. The chemical synthesis method synthesizes cordycepin by chemically modifying adenosine or nucleotide precursors. The synthetic route is long (multiple protection / deprotection reactions are required), the total yield is low (<30%); toxic reagents (such as organic tin and heavy metal catalysts) are used, which is environmentally friendly; harmful impurities may remain in the product, affecting its medical application. As can be seen from the above, the existing cordycepin preparation methods have the problems of low yield, harsh reaction conditions or the need to use a large amount of catalyst.

[0004] In the Chinese patents with publication numbers CN201810333003.5, CN201810563619.1 and CN202310346165.3, in the disclosed method for preparing cordycepin, the preparation of adenosine intermediate is to react adenosine and trimethyl orthoacetate (or other protecting groups) with a strong acid (methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, sulfuric acid) or other basic compounds (4-dimethylaminopyridine (DMAP), dicyclohexylcarbodiimide (DDC), N,N'-diisopropylcarbodiimide (DIC), 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC··), 1,8-diazabicycloundec-7-ene (DBU), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TB D), phosphazene P2-t-Bu solution (tBu-P2), trans-2-[3-(4-tert-butylphenyl)-2-methyl-2-propenyl]malononitrile (DCTB) as catalysts for cyclization reaction to prepare adenosine intermediates: the solvents required for subsequent halogenation and debromination reactions (dimethyl sulfoxide, N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dichloromethane, dichloroethane, acetonitrile, acetone, tetrahydrofuran) face the problems of complex reaction system and difficult post-processing. It is often necessary to use palladium carbon catalysis, use tin reagents with greater toxicity, or phosphoric acid and hypophosphorous acid reagents with greater acidity, causing environmental pollution. In addition, the existing cordycepin preparation methods have the problems of low yield, harsh reaction conditions or the need to use expensive catalysts. Summary of the invention

[0005] 1. Technical issues to be resolved

[0006] In view of the above-mentioned shortcomings and deficiencies of the prior art, the present invention provides a catalyst for cordycepin, which includes red phosphorus and / or black scale; it can replace and reduce the use of toxic reagents and reduce costs;

[0007] Accordingly, the present invention also provides a method for preparing cordycepin, which avoids the use of catalysts through photocatalytic dehalogenation reaction and improves the yield and efficiency of high cordycepin synthesis;

[0008] Correspondingly, the present invention also provides a cordycepin with a purity of more than 95%.

[0009] (II) Technical Solution In order to achieve the above-mentioned purpose, the main technical solution adopted by the present invention includes:

[0010] In a first aspect, the present invention provides a catalyst for cordycepin, comprising red phosphorus and / or black scale.

[0011] In an alternative embodiment, the catalyst may also be a composite material of red phosphorus and a metal organic framework (MOF).

[0012] Currently, red phosphorus is used as a reducing agent. In the existing cordycepin preparation technology, red phosphorus and black phosphorus have not been reported to be directly used as catalysts for deacetylation or nucleoside modification reactions. Their applications are mostly limited to the role of reducing agents and are inefficient.

[0013] Among them, black phosphorus needs to be prepared by converting white phosphorus through high temperature and high pressure, which is costly and dangerous. Poor stability: easy to oxidize (need inert atmosphere protection), limiting its industrial application. Therefore, red phosphorus is preferred as the catalyst for cordycepin.

[0014] The present invention solves the contradiction between efficiency and environmental protection by regulating the morphology or reaction interface of the phosphorus catalyst. One of the principles of the catalyst is that free radicals are generated under light irradiation and transferred to a reducing agent (such as Rongalite as a reducing agent can generate sulfur dioxide free radicals). The free radicals further reduce intermediates such as halogenated adenosine to promote the production of cordycepin.

[0015] In a second aspect, the present invention further provides a method for preparing cordycepin, which comprises the following steps:

[0016] The cordycepin is prepared by reduction reaction of the halogenated product of organic acylated adenosine, a catalyst and a reducing agent under light irradiation.

[0017] The present invention promotes the dehalogenation reaction through a photocatalytic mechanism under the irradiation of light. Under the irradiation of light, the halide ions in the halogenated product are effectively removed to form cordycepin. The light irradiation can excite red phosphorus to produce free radicals, which are transferred to a reducing agent (such as Rongalite to produce sulfur dioxide free radicals) through electrons. The free radicals further reduce the halogenated adenosine intermediates, thereby improving the selectivity and rate of the dehalogenation reaction. Through the photocatalytic reaction, not only can the efficiency of the reaction be significantly improved, but also the use of traditional metal catalysts can be reduced, thereby realizing green chemistry. In particular, the present invention uses light irradiation and can achieve efficient preparation of cordycepin through cheap catalysts such as red phosphorus.

[0018] Among them, cordycepin precursors (such as acetylated adenosine) or catalysts have weak absorption of visible light and rely on ultraviolet light (high energy consumption and expensive equipment). Deacetylation reactions may be accompanied by side reactions (such as ribose ring breakage and amino oxidation), resulting in decreased product purity. Photogenerated carriers (electron-hole pairs) randomly attack different sites of the substrate, making it difficult to accurately control the deacetylation position. The present invention further limits the catalyst to red phosphorus and / or black scale to overcome the above-mentioned technical problems, and cordycepin can be stably obtained, and the purity of cordycepin can reach more than 95%, with a yield of up to 82%.

[0019] In an optional embodiment of the preparation method of the present invention, the organic acylated adenosine includes but is not limited to: monoacylated adenosine, diacylated adenosine or polyacylated adenosine;

[0020] Monoacylated adenosine includes, but is not limited to: 3'-O-acetyladenosine, 3'-O-isobutyryladenosine;

[0021] Diacylated or polyacylated adenosine include, but are not limited to: 2',3'-di-O-acylated adenosine, 2',5'-di-O-acylated adenosine;

[0022] In an optional scheme of the preparation method of the present invention, the optical intensity range of the light is: 30 to 200w.

[0023] In an optional scheme of the preparation method of the present invention, the wavelength range of the light is: 350-500nm.

[0024] In an optional scheme of the preparation method of the present invention, the time of the reduction reaction under light irradiation is 10 to 14 hours.

[0025] In an optional scheme of the preparation method of the present invention, the reducing agent includes one or a combination of two or more of Rongalite, sodium bisulfite, sodium thiosulfite and sodium metabisulfite.

[0026] Among them, Rongalite is also known as sodium bisulfite formaldehyde (rongalite). It is cheap, safe and easy to obtain, and is white rhombic crystals or small pieces. It has strong reducing properties at high temperatures. Red phosphorus, also known as red phosphorus, is a purple-red amorphous powder, shiny, non-toxic, cheap and easy to obtain. It begins to melt when heated to 590°C under high pressure. If it is not pressurized, it will not melt but sublimate, and then condense to obtain white phosphorus after vaporization. In the present invention, red phosphorus is used as a catalyst to promote the dehalogenation reaction through a photocatalytic mechanism under the irradiation of light. In particular, in the technical solution of the present invention, Rongalite is selected as a reducing agent compared to other reducing agents, which can significantly improve the synthesis efficiency of cordycepin and greatly reduce the cost.

[0027] In an optional scheme of the preparation method of the present invention, the mass ratio of the halogenated product, the reducing agent and the catalyst is 1:1-1.2:5-10.

[0028] In an optional scheme of the preparation method of the present invention, 1,2-diaminonaphthalene and a solvent are further added into the reduction reaction.

[0029] The amount of 1,2-diaminonaphthalene added is 0.05 to 0.1 of the weight of the halogenated product;

[0030] The amount of solvent added is 1.8 to 2.2 of the weight of the halogenated product;

[0031] The solvent of the present invention includes a combination of one or more of the following: acetonitrile, DMSO, and DMF.

[0032] In an optional scheme of the preparation method of the present invention, an alkaline reagent is further added to the reduction reaction, and the alkaline reagent includes a combination of one or more of the following: 3, potassium carbonate, sodium carbonate, DIPEA.

[0033] The amount of alkaline reagent added is 1.4 to 180 of the weight of the halogenated product;

[0034] In an optional scheme of the preparation method of the present invention, the preparation method of the halogenated product comprises the following steps: dissolving adenosine and an organic ester compound in acetic acid, reacting at 50 to 65° C. for 10 to 14 hours to obtain acetylated adenosine; and halogenating the acetylated adenosine with a halogenating agent for 10 to 14 hours to obtain the halogenated product.

[0035] The organic ester compound in the present invention is various orthoester compounds such as trimethyl orthoacetate and triethyl acetate.

[0036] In an optional embodiment of the preparation method of the present invention, the halogenation reagent includes but is not limited to acetyl halide.

[0037] The weight volume ratio of adenosine, organic ester compound, acetic acid and halogenating agent is: 10g: 4-8mL: 15-25mL: 8-12mL.

[0038] The acetylated adenosine is dissolved in a solvent (including but not limited to acetonitrile), and a halogenating agent is added dropwise to carry out the reaction. The weight-to-volume ratio of adenosine to acetonitrile is 10 g: 15-25 mL.

[0039] In an optional scheme of the preparation method of the present invention, after the halogenation reaction, ice water is added, and the pH is adjusted to alkaline, and then the halogenated product is obtained by extraction.

[0040] The weight volume ratio of ice water added to adenosine is 1 g: 18-22 mL.

[0041] The present invention dissociates the halogenated product in the reaction system under alkaline conditions and extracts it, which may be extracted with ethyl acetate, thereby removing by-products that may be generated during the reaction and improving the purity of the halogenated product.

[0042] Through methanol recrystallization, the target product cordycepin can be further purified, unreacted residues and impurities can be removed, and finally high-purity cordycepin can be obtained, which can meet the requirements for medicinal use.

[0043] In a second aspect, the present invention also provides cordycepin prepared by the preparation method of cordycepin described in any of the above schemes.

[0044] (III) Beneficial effects

[0045] The beneficial effects of the present invention are:

[0046] The invention uses black scale or red phosphorus in the preparation method of cordycepin, which can improve the yield of cordycepin and reduce or replace the use of harmful chemical substances.

[0047] The preparation method of the present invention uses black scale or red phosphorus as a catalyst and combines it with light catalysis to accelerate the dehalogenation reaction to obtain a yield of more than 65% of cordycepin, and the purity of the product can reach more than 95%; wherein the yield is calculated as M (cordycepin) / M (adenosine).

[0048] Among them, the further use of Rongalite as a reducing agent not only improves the reaction efficiency, but also reduces the dependence on metal catalysts, which meets the requirements of green chemistry. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 The structure diagram of cordycepin prepared in Examples 4-7 of the present invention;

[0050] Figure 2 Schematic diagram of the structure of adenosine in Example 1-3. DETAILED DESCRIPTION

[0051] In order to explain in detail the possible application scenarios, technical principles, specific schemes that can be implemented, and the purposes and effects that can be achieved, the following is a detailed description of the specific embodiments listed in conjunction with the accompanying drawings. The embodiments described herein are only used to more clearly illustrate the technical solutions of the present application, and are therefore only used as examples, and cannot be used to limit the scope of protection of the present application.

[0052] Reference to "embodiment" herein means that the specific features, structures or characteristics described in conjunction with the embodiment may be included in at least one embodiment of the present application. The term "embodiment" appearing in various places in the specification does not necessarily refer to the same embodiment, nor does it particularly limit its independence or association with other embodiments. In principle, in the present application, as long as there is no technical contradiction or conflict, the various technical features mentioned in the embodiments can be combined in any way to form a corresponding implementable technical solution.

[0053] Unless otherwise defined, the technical terms used in this document have the same meanings as those generally understood by those skilled in the art to which this application belongs; the use of relevant terms in this document is only for describing specific embodiments and is not intended to limit this application.

[0054] In the description of this application, the term "and / or" is an expression used to describe the logical relationship between objects, indicating that three relationships may exist, for example, A and / or B, which means: A exists, B exists, and A and B exist at the same time. In addition, the character " / " in this article generally indicates that the objects before and after are in an "or" logical relationship.

[0055] In the present application, terms such as “first” and “second” are merely used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship of quantity, priority or sequence between these entities or operations.

[0056] Without further limitations, in this application, the words "include", "comprises", "has" or other similar expressions used in the sentences are intended to cover non-exclusive inclusion. These expressions do not exclude the presence of additional elements in the process, method or product including the elements, so that the process, method or product including a series of elements may include not only those limited elements, but also other elements not explicitly listed, or also include elements inherent to such process, method or product.

[0057] Similar to the understanding in the Examination Guidelines, in this application, expressions such as "greater than", "less than", "exceed" and the like are understood to exclude the number itself; expressions such as "above", "below", "within" and the like are understood to include the number itself. In addition, in the description of the embodiments of this application, "multiple" means more than two (including two), and similar expressions related to "multiple" are also understood in this way, such as "multiple groups", "multiple times", etc., unless otherwise clearly and specifically limited.

[0058] In the description of the embodiments of the present application, space-related expressions used, such as "center", "longitudinal", "lateral", "length", "width", "thickness", "up", "down", "front", "back", "left", "right", "vertical", "horizontal", "vertical", "top", "bottom", "inside", "outside", "clockwise", "counterclockwise", "axial", "radial", "circumferential", etc., indicate the orientation or position relationship based on the orientation or position relationship shown in the specific embodiments or drawings, and are only for the convenience of describing the specific embodiments of the present application or facilitating the reader's understanding, and do not indicate or imply that the referred device or component must have a specific position, a specific orientation, or be constructed or operated in a specific orientation, and therefore cannot be understood as a limitation on the embodiments of the present application.

[0059] Unless otherwise expressly specified or limited, in the description of the embodiments of the present application, the terms such as "install", "connect", "connect", "fix", "set", etc. used should be understood in a broad sense. For example, the "connection" can be a fixed connection, a detachable connection, or an integrated setting; it can be a mechanical connection, an electrical connection, or a communication connection; it can be a direct connection, or it can be indirectly connected through an intermediate medium; it can be the internal connection of two elements or the interaction relationship between two elements. For technicians in the technical field to which the present application belongs, the specific meanings of the above terms in the embodiments of the present application can be understood according to the specific circumstances.

[0060] Example 1

[0061] This embodiment provides a method for preparing a brominated product of acetylated adenosine, the steps of which are:

[0062] 1000g of adenosine (structural formula: Figure 2 ) and 600 mL of trimethyl orthoacetate were dissolved in 2000 mL of acetic acid, reacted at 60°C for 5 h, acetic acid was distilled off under vacuum, and the remaining product was dissolved in 2000 mL of acetonitrile, 1000 mL of acetyl bromide was added dropwise at zero degrees Celsius, and reacted for 6 h; the reactant was introduced into 2000 mL of ice water and the pH was adjusted to alkaline with sodium bicarbonate. It was extracted three times with ethyl acetate, the product was dried and spin-dried, and then recrystallized with methanol to obtain the brominated product.

[0063] In this example, under the condition of 60° C., trimethyl orthoacetate can effectively react with adenosine to generate an acetylated product; the addition of peracetyl bromide utilizes the electronegativity of the bromine atom to enhance its nucleophilicity, replaces the oxygen group on the adenosine molecule, and efficiently forms a brominated product.

[0064] The method of this embodiment can be applied to the preparation of brominated products of other organic acylated adenosines.

[0065] Example 2

[0066] This embodiment provides a method for preparing a brominated product of acetylated adenosine, the steps of which are:

[0067] 1000g of adenosine and 800mL of trimethyl orthoacetate were dissolved in 1500mL of acetic acid, reacted at 65°C for 4h, acetic acid was distilled off under vacuum, and the remaining product was dissolved in 1500mL of acetonitrile, 1200mL of acetyl bromide was added dropwise at zero degrees Celsius, reacted for 6h, introduced into 1200mL of ice water and the pH was adjusted to alkaline with sodium bicarbonate. The product was extracted three times with ethyl acetate, dried and spin-dried, and then recrystallized with methanol to obtain the brominated product.

[0068] Example 3

[0069] This embodiment provides a method for preparing a brominated product of acetylated adenosine, the steps of which are:

[0070] 1000 g of adenosine and 400 mL of trimethyl orthoacetate were dissolved in 2500 mL of acetic acid, reacted at 50°C for 10 h, then 800 mL of acetyl bromide was added dropwise at zero degrees Celsius without adding other solvents, reacted for 14 h, introduced the reactants into 1800 mL of ice water and adjusted the pH to alkaline with sodium bicarbonate. The product was extracted three times with ethyl acetate, dried and spin-dried, and then recrystallized with methanol to obtain the brominated product.

[0071] The brominated product of acetylated adenosine obtained by the method of Examples 1-3 of the present invention does not require the use of a catalyst during the reaction process. This method can simply condense the two-step reaction into a one-step method, only requires acetic acid as a solvent, and does not require the use of other solvents. The method is simple to operate and does not require other post-treatment in the first step.

[0072] Example 4

[0073] This embodiment provides a method for preparing cordycepin, the steps of which are:

[0074] 207 g (1.0 equiv.) of brominated product of acetylated adenosine, 230 g (3.0 equiv.) of Rongalite, 12 g (0.2 equiv.) of red phosphorus, 16 g (0.2 equiv.) of 1,2-diaminonaphthalene, 3 324 g (3.0 equiv.) was added to the reaction vessel, and 500 mL of DMA was added. Under light (wavelength 450 nm, optical intensity 100 W),

[0075] ) was irradiated for 12 h, filtered after the reaction, extracted with water, and the solvent was dried and recrystallized with methanol; Figure 1 The structure of cordycepin is shown.

[0076] In the method of this embodiment, the yield of cordycepin reaches 65%. The yield calculation formula is: yield = M (cordycepin) / M (adenosine)

[0077] Example 5

[0078] This embodiment provides a method for preparing cordycepin, which is different from that of Embodiment 4 in that some parameters and reagents are different, and the specific steps are as follows:

[0079] 100 parts by weight of the brominated product of acetylated adenosine, 120 parts by weight of Rongalite, 5 parts by weight of red phosphorus, 10 parts by weight of 1,2-diaminonaphthalene, and 140 parts by weight of potassium carbonate are added to a reaction container, and 220 parts by volume of acetonitrile are added, and the mixture is reacted for 14 hours under irradiation of purple light (wavelength 380 nm, optical intensity 50 w). After the reaction is completed, the mixture is filtered, extracted with water, and the solvent is dried by spin drying and then recrystallized with methanol; deprotection is performed using an ammonia methanol solution (3 hours) to obtain the compound as shown in the following example. Figure 1 The structure of cordycepin is shown.

[0080] Example 6

[0081] This embodiment provides a method for preparing cordycepin, which is different from that of Embodiment 4 in that some parameters are different and reagents are different. The specific steps are as follows:

[0082] 100 parts by weight of the brominated product of acetylated adenosine, 100 parts by weight of Rongalite, 10 parts by weight of red phosphorus, 5 parts by weight of 1,2-diaminonaphthalene, and 180 parts by weight of sodium carbonate are added to a reaction container, and 180 parts by volume of DMSO solvent is added, and the reaction is carried out under blue light (wavelength 500nm, optical intensity 100w) for 10 hours. After the reaction is completed, the reaction is filtered, water is added for extraction, the solvent is spin-dried, and then recrystallized with methanol; deprotection is carried out using an ammonia methanol solution (3 hours) to obtain Figure 1 The structure of cordycepin is shown.

[0083] Example 7

[0084] This embodiment provides a method for preparing cordycepin, which is different from that of Embodiment 4 in that some parameters are different and some reagents are different. The specific steps are as follows:

[0085] 100 parts by weight of the brominated product of acetylated adenosine, 110 parts by weight of Rongalite, 7 parts by weight of red phosphorus, 8 parts by weight of 1,2-diaminonaphthalene, and 160 parts by weight of DIPEA are added to a reaction container, and 200 parts by volume of DMF are added, and the reaction is carried out under blue light (wavelength 450nm, optical intensity 100w) for 12h. After the reaction is completed, the mixture is filtered, extracted with water, and the solvent is dried by spin drying and then recrystallized with methanol; deprotection is carried out using an ammonia methanol solution (3h) to obtain Figure 1 Compared with the cordycepin synthesis yield of 14%-45% by other methods, the cordycepin preparation method of Examples 4-7 of the present invention can achieve a maximum yield of 65%.

[0086] The preparation method of cordycepin in Examples 4-7 of the present invention can use, but is not limited to, the brominated product of acetylated adenosine prepared in Examples 1-3. In particular, the present invention uses the brominated product prepared in Examples 1-3 to prepare cordycepin, and the reaction efficiency under subsequent light irradiation is significantly higher.

[0087] Example 8

[0088] This embodiment provides a method for preparing cordycepin, which is different from that of Embodiment 4 in that red phosphorus is replaced by black scale in the same mass fraction.

[0089] Example 9

[0090] This embodiment provides a method for preparing cordycepin, which is different from that of embodiment 4 in that the reaction is carried out under dual-wavelength alternating illumination. The reaction is carried out for 12 hours under alternating illumination of a light source with a wavelength of 450nm and an optical intensity of 100W and a light source with a wavelength of 500nm and an optical intensity of 200W (after irradiating with each light source for one hour, the other light source is started to alternate).

[0091] The yield of cordycepin in this example is significantly improved due to the use of alternate light irradiation.

[0092] In addition, in the preparation methods of Examples 4-9 of the present invention, the use of photocatalysis, red phosphorus / black scale and Rongalite reduction reactions not only significantly improved the synthesis yield of cordycepin, but also improved the green chemical characteristics of the reaction.

[0093] Example 9

[0094] In order to better demonstrate the beneficial effects of Examples 1-9 of the present invention compared with the prior art, the following experiments were conducted and corresponding experimental results were obtained.

[0095] In the following experiments: the brominated product of acetylated adenosine in Example 4 was prepared by the method of Example 1.

[0096] Experiment 1:

[0097] When the reducing agent in the preparation method of Example 4 is replaced by any one of sodium borohydride, sodium cyanoborohydride, borane, and lithium aluminum hydride in equal weight parts, the reaction does not produce the corresponding target product. When the reducing agent is replaced by one of sodium bisulfite, sodium thiosulfate, and sodium pyrosulfite as the reducing agent, the yield of cordycepin is only 15-35%.

[0098] As can be seen from the above, when the reducing agent in the present invention is Rongalite, compared with other reducing agents, it can significantly improve the synthesis efficiency of cordycepin, which is a qualitative improvement and has unexpected technical effects. Under the action of light, the combination of Rongalite, the brominated product of acetylated adenosine and red phosphorus has a positive contribution to the yield of cordycepin. The use of Rongalite is not a simple replacement of the reducing agent. In particular, the technical solution of the present invention, in a weakly alkaline aqueous solution, Rongalite decomposes to generate sulfoxylate (HSO 2 - ) and formaldehyde (CH 2 O); at the same time, under light, Rongalite decomposes to generate HSO 2 - with·SO 2 - Formation of a double reduction system: HSO 2 - : Selective deacetylation via a nucleophilic mechanism; SO 2 - : Rapidly reduce intermediates through single electron transfer and inhibit side reactions (such as the formation of oxidation byproducts). Light promotes the 2 O) into CH 2O free radicals form a hydrogen bond network with the ribose hydroxyl group, stabilize the transition state and accelerate the deacetylation process. It can be seen that the combined use of Rongalite and red phosphorus has a synergistic effect on the yield and speed of cordycepin in the present invention.

[0099] Experiment 2:

[0100] When 1,2-diaminonaphthalene in the preparation method of Example 4 was replaced with the same weight portion of any one of 1,10-phenanthroline, aniline, 1-aminonaphthalene and triphenylphosphine, the reaction could not proceed and cordycepin was not obtained.

[0101] This experiment further proves that 1,2-diaminonaphthalene must be added in the preparation method of cordycepin of the present invention. Compared with the prior art, the present invention provides a new preparation method of cordycepin, in particular, it uses red phosphorus or black scale as a catalyst, preferably Rongalite as a reducing agent, and 1,2-diaminonaphthalene must be added to make the reaction proceed.

[0102] Experiment 3:

[0103] When sodium bicarbonate in the preparation method of Example 4 is replaced by any one of potassium tert-butoxide, sodium tert-butoxide, potassium acetate, sodium acetate, and sodium dihydrogen phosphate, the reaction cannot proceed and cordycepin is not obtained. When sodium bicarbonate is not added to the reaction, the reaction cannot proceed.

[0104] The experimental results show that the addition of sodium bicarbonate in the present invention is necessary, and the reaction can only proceed when the pH value is adjusted using sodium bicarbonate.

[0105] In particular, it uses red phosphorus or black scale as a catalyst, preferably Rongalite as a reducing agent, and must add 1,2-diaminonaphthalene. The combination of sodium bicarbonate overcomes the technical barriers of preparing cordycepin by the photocatalytic method of the brominated product of acetylated adenosine.

[0106] Experiment 4:

[0107] In the preparation method of Example 4, when a 350nm, 100W ultraviolet lamp is used as the light source, the yield of cordycepin is only 41%;

[0108] In the preparation method of Example 4, when a 350nm, 200W ultraviolet lamp is used as the light source, the yield of cordycepin is only 54%;

[0109] In the preparation method of Example 4, when a 500nm, 100W lamp is used as the light source, the yield of cordycepin is only 52%;

[0110] In the preparation method of Example 4, when a 500nm, 30W lamp is used as the light source, the yield of cordycepin is only 24%;

[0111] In the preparation method of Example 4, when a 30W blue light is used as the light source, the yield of cordycepin is only 26%;

[0112] In the preparation method of Example 4, when a 200W blue light is used as the light source, the yield of cordycepin reaches 82%;

[0113] In the preparation method of Example 4, when there is no light, the reaction cannot proceed.

[0114] From the results of this experiment, it can be seen that the light synthesis process of cordycepin is sensitive to the wavelength and intensity of light, especially when blue light is used as the light source, the yield is qualitatively improved.

[0115] Experiment 5: When no additive is added to the reaction, the reaction cannot proceed.

[0116] In summary, in the preparation method of cordycepin provided by the present invention, the halogenated product of organic acylated adenosine is successfully prepared into cordycepin under the action of light, catalyst and reducing agent. In particular, using blue light as the light source, Rongalite as the reducing agent and red phosphorus as the catalyst has a synergistic effect on the yield and generation rate of cordycepin, the effect is qualitatively improved, and has unexpected technical effects.

[0117] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A catalyst for cordycepin, characterized in that: It includes red phosphorus and / or black scale.

2. A method for preparing cordycepin, characterized in that: It includes the following steps: The cordycepin is prepared by reduction reaction of the halogenated product of organic acylated adenosine, a reducing agent and a catalyst under light irradiation.

3. The method for preparing cordycepin according to claim 2, characterized in that: The wavelength range of light is: 380~500nm.

4. The method for preparing cordycepin according to claim 2, characterized in that: The reduction reaction time under light irradiation is 10 to 14 hours.

5. The method for preparing cordycepin according to claim 2, characterized in that: The reducing agent includes one or a combination of two or more of Rongalite, sodium bisulfite, sodium thiosulfite and sodium pyrosulfite.

6. The method for preparing cordycepin as claimed in claim 2, characterized in that: The mass ratio of the halogenated product, the reducing agent and the catalyst is 1:1-1.2:5-10.

7. The method for preparing cordycepin as claimed in claim 2, characterized in that: 1,2-diaminonaphthalene and a solvent are also added into the reduction reaction.

8. The method for preparing cordycepin as claimed in claim 2, characterized in that: An alkaline reagent is also added to the reduction reaction, and the alkaline reagent includes a combination of one or more of the following: Net3, potassium carbonate, sodium carbonate, and DIPEA.

9. The method for preparing cordycepin according to claim 2, characterized in that: The preparation method of the halogenated product comprises the following steps: dissolving adenosine and an organic ester compound in acetic acid, reacting at 50-65° C. for 10-14 hours to obtain acetylated adenosine; and halogenating the acetylated adenosine with a halogenating agent for 2-5 hours to obtain the halogenated product.

10. Cordycepin prepared by the method for preparing cordycepin according to any one of claims 1 to 9.

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